A number of xanthine derivatives exhibit biological activity. These derivatives are generally 1, 3 or 7 lower alkyl-substituted, and their activity varies depending upon which of these positions of the xanthine nucleus are alkylated. For example, theophylline, theobromine and caffeine differ from one another solely by the location of methyl groups at these three sites.
Theophylline is a particularly important biologically active xanthine derivative (1,3-dimethylxanthine). Theophylline is a bronchodilator which can be useful in the treatment of asthma. The importance of monitoring theophylline levels is illustrated by the finding of widely varying serum theophylline concentrations in patients receiving identical doses. Since theophylline is metabolized in the liver, factors which affect the liver may affect theophylline metabolism resulting in modified serum half-lifes. Factors such as cigarette smoking, chronic theophylline therapy, alcoholism, barbiturates, allopurinol, and impaired hepatic or renal function may lead to toxic or inadequate dosing. Differences in serum levels between individuals may arise from the drug form used (tablet, suppository, elixir), site administration (oral, rectal), and rate and quantity of theophylline absorbed. This is in part a result of the low solubility of theophylline in the gastrointestinal environment.
Titering of serum theophylline levels is particularly important in infant care because premature infants have a greater sensitivity to adverse side effects of high theophylline levels and because the serum half-life of theophylline in premature infants is longer and more variable than in adults or older children.
Gas liquid chromatography, high pressure liquid chromatography and spectrophotometry have been used to determine concentrations of theophylline and other xanthine derivatives. These techniques tend to be more labor intensive and less rapid for multisample batch sizes than radioimmunoassay methods.
Radioimmunoassay requires smaller sample sizes than the above methods. This is an advantage for titering theophylline levels in premature infants. However, prior radioimmunoassay methods for theophylline have employed tritiated theophylline as tracer. This has necessitated the use of scintillation counting of tritium, a considerably less convenient technique than gamma counting of iodine isotopes. Tritium labeled tracers also have a lower specific activity than iodinated tracers, thus limiting the sensitivity of the radioimmunoassay. Finally, tritium may have a tendency to exchange with hydrogen ions in solution depending upon the substitution site.
It is therefore an object of this invention to provide new xanthine derivatives which are useful in the preparation of tracers for the radioimmunoassay of theophylline and related compounds.
It is a further object of this invention to provide radioiodinated xanthine derivatives useful as tracers in the radioimmunoassay of theophylline and related compounds.
These and other objects of this invention will be apparent to those skilled in the art from a consideration of this specification taken in its entirety.